Primary cytotoxic T cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway

Background: Primary cytotoxic T cell lymphomas are a heterogenous collection of ill-defined diseases with aggressive disease course and poor response to conventional therapy. Of these, primary cutaneous CD8+ aggressive epidermotropic T cell lymphoma and cutaneous T cell lymphoma, not otherwise specified, have undergone few to no systematic analyses of its genetic landscape. In this study, we classify these lymphomas based on their histological and clinical features and perform systematic genomic analyses to find novel therapeutic targets. Methods: We clinically characterize 35 patients from 10 institutions with cytotoxic T cell lymphoma and performed integrative clinical, pathological, and genetic analyses. We perform Archer™ Heme Fusion on an initial 24 FFPE samples. In addition, we perform DNA and/or RNA sequencing on 11 cases. We functionally validate our genetic findings by transducing alterations into Ba/F3 cells and subsequently performing biochemical assays. In this setting, we assess sensitivity to FDA-approved small molecule inhibitors. We provide orthogonal evidence of transcriptional upregulation by geneset enrichment analysis. Results: We find kinase fusions impacting JAK-STAT signaling in all primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our cohort. Three of these fusions have not previously been described in cancer. Known fusions have been shown to upregulate JAK-STAT signaling. Upon each transduction, CAPRIN1-JAK2 and SELENOI-ABL1 cause increased phosphorylation and display IL-3-independent growth compared to control. Upon treatments to small molecule inhibitors, ruxolitinib and imatinib respectively, CAPRIN1-JAK2 and SELENOI-ABL1 expressing cells exhibit sensitivity. Cutaneous T cell lymphoma, not otherwise specified, harbor JAK-STAT hotspot mutations but not kinase fusions. Conclusions: All 9 primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our series harbor kinase fusions, while the majority of the cutaneous T cell lymphoma, not otherwise specified, cases in our cohort harbor hotspot JAK/STAT mutations. We provide evidence that the of presence these alterations, which are associated with inhibitor response, depend on cytotoxic T cell lymphoma histology.